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Proteogenomic integration reveals therapeutic targets in breast cancer xenografts

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Item Type:Article
Title:Proteogenomic integration reveals therapeutic targets in breast cancer xenografts
Creators Name:Huang, K.L. and Li, S. and Mertins, P. and Cao, S. and Gunawardena, H.P. and Ruggles, K.V. and Mani, D.R. and Clauser, K.R. and Tanioka, M. and Usary, J. and Kavuri, S.M. and Xie, L. and Yoon, C. and Qiao, J.W. and Wrobel, J. and Wyczalkowski, M.A. and Erdmann-Gilmore, P. and Snider, J.E. and Hoog, J. and Singh, P. and Niu, B. and Guo, Z. and Sun, S.Q. and Sanati, S. and Kawaler, E. and Wang, X. and Scott, A. and Ye, K. and McLellan, M.D. and Wendl, M.C. and Malovannaya, A. and Held, J.M. and Gillette, M.A. and Fenyö, D. and Kinsinger, C.R. and Mesri, M. and Rodriguez, H. and Davies, S.R. and Perou, C.M. and Ma, C. and Townsend, R.R. and Chen, X. and Carr, S.A. and Ellis, M.J. and Ding, L.
Abstract:Recent advances in mass spectrometry (MS) have enabled extensive analysis of cancer proteomes. Here, we employed quantitative proteomics to profile protein expression across 24 breast cancer patient-derived xenograft (PDX) models. Integrated proteogenomic analysis shows positive correlation between expression measurements from transcriptomic and proteomic analyses; further, gene expression-based intrinsic subtypes are largely re-capitulated using non-stromal protein markers. Proteogenomic analysis also validates a number of predicted genomic targets in multiple receptor tyrosine kinases. However, several protein/phosphoprotein events such as overexpression of AKT proteins and ARAF, BRAF, HSP90AB1 phosphosites are not readily explainable by genomic analysis, suggesting that druggable translational and/or post-translational regulatory events may be uniquely diagnosed by MS. Drug treatment experiments targeting HER2 and components of the PI3K pathway supported proteogenomic response predictions in seven xenograft models. Our study demonstrates that MS-based proteomics can identify therapeutic targets and highlights the potential of PDX drug response evaluation to annotate MS-based pathway activities.
Keywords:Breast Neoplasms, Molecular Targeted Therapy, Phosphorylation, Proteogenomics, Signal Transduction, Transcriptome, Xenograft Model Antitumor Assays, Animals, Mice
Source:Nature Communications
ISSN:2041-1723
Publisher:Nature Publishing Group (U.K.)
Volume:8
Page Range:14864
Date:28 March 2017
Additional Information:Corrigendum: The original version of this Article contained a typographical error in the spelling of the author Beifang Niu, which was incorrectly given as Beifung Niu. This has now been corrected in both the PDF and HTML versions of the Article.
Official Publication:https://doi.org/10.1038/ncomms14864
PubMed:View item in PubMed

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